3-enol ethers of 6-hydroxymethyl-3-oxo-delta4-steroids and process for their preparation



United States Patent 3,095,411 3-ENOL ETHERS 0F 6-HYDROXYMETHYL-3-0X0- zit-STEROIDS AND PROCESS FOR THEIR PREP- ARATION David Neville Kirk and Vladimir Petrow, London, England, assignors to The British Drug Houses Limited No Drawing. Filed Nov. 6, 1961, Ser. No. 150,176 Claims priority, application Great Britain Nov. 7, 1960 31 Claims. (Cl. 260-23955) This invention is for improvements in or relating to organic compounds and has particular reference to steroidal materials containing anvadditional carbon substituent at C It is an object of the present invention to provide a new and general process for the preparation of a new series of steroidal products which may be regarded structurally as the 3-en'ol ethers of G-hydroxymethyl-S-oxo- A -steroids.

We have made the surprising discovery that the steroidal products of our copending application No. 150,140 filed November 6, 1961 which may be regarded structurally as the 3-enol ethers of 6-formy1-3-oxo-A -steroids may be converted by the process of this invention into the corresponding 6-hydroxy methyl derivatives.

This is a discovery of outstanding importance in the field of steroid technology. Many of the herein described derivatives possess valuable biological properties which render them of value in, for example, the veterinary field. Thus, for example, the derivatives of 175- hydroxyanrirostane which tall within the scope of the present invention may possess anabolic, androgenic and claudogenic properties. The derivatives of l7a-acyloxypregnan-ZO-one which fall within the scope of the present invention may possess progestational properties when administered 'by the oral route. The derivatives of 160:,17aisopropylidenedioxypregnan-ZO-one may likewise show progestational activity as -well as claudogenic activity. Claudogenic activity will, in general, also be shown by derivatives of 90a -fluoropregnan-l1B,-17u,21-trihydroxy- 20-on'e, l7or,2l-dihydroxypregnane-l1,20-dione, 11,8,17a, 21-trihydroxypregnane-20-one and by the 2l-acyl and 17,21-di acylderivatives thereof. In addition, such compounds may show glucocorticoid activity.

The compounds of the present invention form exceptionally convenient intermediates for the preparation of the therapeutically valuable Got-methyl steroidal hormones of the androstane and pregnane series, which compounds are now well-known in clinical practice, and into which they maybe converted by the following series of transformations. Firstly, by treatment with H+ ions, they are transformed into the corresponding 6-methylene- 3-oxo-A -steroids. The last group of compounds on catalytic hydrogenation followed by treatment with very di lute ethanolic hydrochloric acid, or potassium hydroxide, then yields the requisite 6a-methyl-3-oxo-A -steroids. In addition the products of the present invention represent entirely new types of steroidal materials which themselves possess intrinsic value as building blocks for other types of steroidal materials containing a C carbon substituent. Thus, for example, they may be expected to react with a variety of reagents such as the halogens, peracids and to undergo hydrogenation. The numerous possibilities for reaction possessed by the products of the present invention will be apparent to those skilled in the art.

It is a further object of the present invention to pro- 3,095,41 1 Patented June 25, 1963 vide pharmaceutical preparations of the biologically active materials.

The present invention provides new 3-eno1 ethers of 6-hydroxymethyl-3-oxo-A -steroids including the Formula I below.

The invention provides the following new products:

21 acetoxy-3-ethoxy-17e-hydroxy-o-hydroxymethylpregna-3,5-diene-11,20-dione ZI-acetoxy 17oz hydroxy-6-hydroxymethyl-3-methoxypregna-3,5-diene-11,20-dione 21-acetoxy 17 a hydroxy 3 [[3 hydroxyethoxy] 6- hydroxymethylpregn'a-3,S-diene-1 1,20-dione 17,21 diacetoxy 6 hydroxymethyl 3 methoxypregna-3,5-:diene-11,20-dione which are of value on account of their claudogenic activity and as intermediates tor the preparation of the corresponding 3-oxo-A -6-methylenic corticoids 17u,21-dihydroxy 6 hydroxymethyl 3 methoxypregna-3,5-diene-l1,20-dione 17,21-acetonide 17,20:20,21-bismethylenedioxy 3 ethoxy 6 hydroxymethylpregna-3,5-diene-1l-one which is of value as an intermediate for the preparation of the corresponding G-met-hylenic corticoid into which it may be converted by procedures described above or by methods of prior art :acetoxy 6 hydroxymethyl 3 methoxy-ltS-methylenepregna-3,S-dien-ZO-one 17a-acetoxy 6 hydroxymethyl 3 methoxypregna-3,5-

dien-ZO-one 17a-acetoxy 6 hydroxymethyl 3 methoxy-l6a-methylpregna-3,5-dien-20-one which are of value on account of their progestational properties 3-e-thoxy-6-hydroxyrnethyl-16a,17a isopropylidenedioxypregna-3,5dien-20-one 6-hydroxymethyl-3-methoxypregna-3,5dien-20-one which are of value on account of their progestational and claudogenic properties 17,8 acetoxy-3-ethoxy-6-hydroxymethy1-2a-methylandrosta- 3,5-diene 17,8 acetoxy 6 hydroxymethyl-3-methoxyandrosta-3,S-

diene 3-ethoxy-6-hydroxy'methyl-17/3-propionoxy 17a (prop- 1 '-ynyl) -androst-a-3,5-diene l'lfl-acetoxy 3 benzyloxy 6 hydroxyme-thylandrosta- 3,5-diene l7fi :acetoxy 3 ethoxy-G-hydroxymethyl-l9-norandrosta-3,5-diene 17B-acetoxy-3-methoxy-6-hydroxymethyl 19 norandrosta-3,5-diene 17 fi-acetoxy 3 ethoxy 6 hydroxymethylandrosta-3,5- diene which are of value on account of their androgenic/anabolic/claudogenic :activity 6-hydroxymethyl-3-methoxy 16 methylpregna 3,5,16-

trien-20-one 20fl-acetoxy-3ethoxy-6-hydroxyrnethylpregna-3,5-diene l1a,17,,8 diacetoxy-6-hydroxymethyl-3-methoxyandrosta- 3,5 -diene 3-ethoxy 6 hydroxymethylpregna 3,5,l7(20)-trien-21- oic acid ethyl ester 6-hydroxymethyl-3-methoxyandrosta-3,5 dien 17 one which are of value as novel intermediates which may be converted into many other novel materials by such procedures as reduction, hydrogenation and oxidation The 3-enol methyl ether of 6-hydroxymethyltestololactone which is of value as an intermediate and on account of its claudogenic activity 21-acetoxy 6 hydroxymethyl 3 methoxypregna 3,5-

lHrOH (I) where R is O-alkyl, O-hydroxyalkyl, O-cycloalkyl, O-alkaryl or a functional derivative thereof which process comprises reducing the corresponding 3-enol ether of a 6-formyl-3-oxo-A -steroid including the formula H (II) where R has the same meaning as above.

A wide variety of reducing agents may be used for converting the 6-formyl derivatives (II) which form the starting materials of the invention, into the 6-hydroxymethyl derivatives (I) which form the products of the present invention. Such reducing agents, however, must :not be acidic in character, nor must they be used in an acidic environment as the resulting 6-hydroxymethyl derivatives (I) are very sensitive to acids which convert them into the corresponding 6-methylene-3-oxo-A steroids.

Conversion of 6-formyl derivatives (II) additionally substituted by systems sensitive to both reduction and alkaline hydrolysis such as .COCH OAc is conveniently achieved oatalytically employing Raney nickel as catalyst. As Raney nickel, as normally prepared, is strongly alkaline in reaction, it is advisable to free it from alkali before use otherwise concomitant hydrolysis of the acylated ketal system may occur. This may be done by any method known to those skilled in the art such, for example, as treating it with ethyl acetate. This method of reduction is generally useful.

Platinum on charcoal in the presence of a sodium acetate buffer represents another valuable catalyst for catalytic hydrogenation. Thus, for example, it may be used to catalytically hydrogenate the 6-formy1 group in such compounds as 21-acetoxy-6-formyl-17a-hydroxy-3- methoxypregna-3,5-diene-11,20-dione and 21-acetoxy-6- formyl-3-methoxypregna-3,5-dien-20-one.

Organometallic hydrides such for example as lithium, sodium, magnesium and calcium borohydrides, lithium aluminium hydride and tritertbutoxy aluminium hydride represent another group of reducing agents which are particularly valuable for reducing the 6-formyl group in 17a-acyloXypregnan-20-one derivatives. Lithium. cyanoborohydride may be valuable in certain instances.

The Ponndorf method of reduction may be employed for reducing 6-formyl derivatives that do not contain additional carbonyl groups. Other methods of reduction may be found in standard works of reference such as Houben-Weyl.

The 6-formyl derivatives (II) which form the starting materials of the present invention are prepared by the process of our copending application No. 150,140. In

4 this process the 3-enol ether of a 3-oXo-A -steroid including the formula (III) (where R has the meaning hereinabove defined) is treated with the Vilsmeir reagent (see Houben-Weyl Methoden der Organische Chemie, 4th ed., 1954, vol. 7(1), page 29 et seq.) preferably at approximately 0 C. and in a solvent such as methylene chloride and the resulting imim'um salt decomposed by pouring in e.g. sodium acetate, when the 6-formyl derivatives (II) :81'6 obtained. As described in our copending application the 6-formyl group may be introduced into the 3-enol ethers of steroidal 3-oxo-A -enes which may be additionally substituted by Hydroxyl and acyloxy groups and functional derivatives thereof in such positions as 11, 12, 16 (including 16- hydroxy methyl), 14, 15, 17, 18, 19, 20 and 21 (including the condensation products of 17a-glYc0lS with carbonyl components). T hiol groups at C are unaffected.

Carbonyl groups such for example as carbonyl groups at11,12,15,16,17,18and20.

Carbalkoxy groups at C C16, C or in the sidechain.

Cyano groups at C C and C Alkyl groups, in particular Me groups at C C11, C

C17, C21, and ethyl at C17.

Alkenyl and alkynyl groups in particular vinyl and allyl at C propynyl and chlorethynyl at C Methylene and ethylidene groups at C C and C groups such as benzylidene at C Lactone, ether and spiroketal residues: Spirolactone residues such as O.CO.CH .CH -attached to C etheric groups at C and bridging C and C spiroketal moieties such as are present in diosgenone, 20,20- ethylenedioxy groups, 17,17-ethylenedioxy groups and similar functional derivatives.

Halogen groups and in particular chlorine and fluorine at C9, C15 and C21.

Unsaturated linkages in particular at C C C C and 11(20)- Ketol groups in particular acylated ketol groups at 1e' 17 17' 2o and 20-21- Cortical side chains, both acylated, or converted into such protective derivatives as bismethylenedioxy, cycliccarbonates, cyclic acetonides or orthoformates.

Epoxides and halohydrins, particularly at C In reducing 6-formyl derivatives containing the foregoing substituents care should be taken by those skilled in the art in the choice of an appropriate reductant.

The process of the invention may be applied to the 6-formyl derivatives derived from the following steroids and acyl derivatives thereof.

Testosterone 2-met-hyltestosterone 17 a-methyltestosterone 9( 11)-dehydro-l7a-methyltestosterone l7a-propynyltestosterone l7a-acyloxyprogesterone 9( 1 1 )dehydro-17a-acyloxyprogesterone 16-methyl- 17 a-acyloxyprogesterone 9( 1 1 )-dehydro-16-methyl-17a-acyloxyprogesterone 16-methylene-17a-acyloxyprogesterone 9(11)-dehydro-16-methylene-l7a-acyloxyprogesterone 17a-acyloXy-l 6-ethylideneprogesterone 16a,17a-dimethylmethylenedioxyprogesterone 9( 1 1 )-dehydro-l6a,17a-dimethylmethylenedioxyprogesterone Cortisone lfiwmethylcortisone 2 1 -methylcortisone lfi-methylcnecortisone tl6czhydroxy cortisone and the (16m, l7a)-acetonide thereof Hydrocortisone 16-methy1hydrocortisone 2 lmethylhydrocortisone 16-methy1enehydrocortisone 16 a-hydroxyhyd-rocortisone and the 1 6a, 17oz) -acetonide thereof 17 11,2 1-dihydroxypregna-4,9 1 1 )-diene-3 ,ZO-dione 16-methyl- 17,2 1-dihydroxypregna-4,9( 1 1 -diene-3 ,20-

dione 21-'met-hyl-17a,-21-dil1ydroxypregna-4,9( 1 1 ediene-3 ,20-

dione 16-methylene-17a,21-di1hydroxypregnla-4,9( 1 1 )-diene-3 20-dione 16u-hydroxy- 17a,2 1-dihydroxypregna-4,9 1 1 -diene-3 ,20-

dione and the 16,17)-a-cetonide thereof 21-fluoro-17a-lhydroxypregna-4,9 1 1 -diene-3,20-dione and the 16, 17) -acetonide thereor 21-fluoro-17a-hydroxypregn-4cne-3,1 1,20-trione and the 16,17) acetonide thereof 21-fluoro-1 1, l7a-dihydroxypregn-4-ene-3 ,20-dione and the 1 6,17) acetonide thereof 21-hydroxypregna-4, 17 -dien-3-one 1 1-oxo-21-hydroxypregna-4, 1 7-dien-3 -one 1 1,2l-dihydroxypregna-4,17-dien-3-one 9( 1 1 )-dehydro-21-1hydroxypregna-4,l7-dien-3-one 3-oxopregna-4,17-dienoic acid (esters) 3,1 1-dioxopregna-4, 17-dienoic acid (esters) 1'-1- hydroxy-3-oxopregna-4,17 -dienoic acid (esters) 9 1 1 -dehydro-3-oxopregna-4, 17-dienoic acid (esters) 2 1 -fluorol 7 aacyloxyprogesterone Progesterone 1 6 -methy1progesterone 1 l-oxoprogesterone 9( 1 1 -dehydroprogesterone ZI-methylprogesterone The 9m-fluoro derivatives of the above lla-hydroxy and 1 Loire-steroids.

Following is a description by way of example of methods of carrying the invention into efiect.

EXAMPLE 1 Preparation of 3-Ethoxy6-Hydroxymethyl-16a,17a-Is0- propylidenedioxypregna-S,5-Dien-20-One Me M6 OH:

Me? P EtO 3 ethoxy 6 formyl 160:,170: isopropylidenedioxypregna-3,5-dien-20-one (2.0 g.) in dry tetrahydrofuran (15 ml.) was stirred with lithium borohydride (300 mg.) for 10 minutes. The mixture was then poured into water and the gummy product thus obtained extracted with ether, the extract washed neutral, dried (sodium sulphate) and evaporated in vacuo. The crystalline solid thus obtained was purified from acetone/hexane (containing a drop of pyridine) to give 3-ethoxy-6-hydroxymethyl- 16a,17a isopropylidenedioxypregna 3,5 dien 20- One, hard leaflets, M.P. 163 to 164 C., a

EXAMPLE 2 Preparation of 17u;20:20,21-Bism'ethylenedioxy-3-Ethoxy- 6-H ydr0xymetlzylpregna-3,5 -Dien-1 1 -One 17u,20:20,21 bismethylenedioxy 3 ethoxy 6 forrnylpregna-3,5-dien-11-one (1 g.) was reduced with sodium borohydride (0.1 g.) in tetrahydrofuran (10 ml.) and methanol (2 ml.) for 15 minutes at room temperature. The reaction mixture was poured into water, the product was extracted into ether, the extract was washed with water, dried over anhydrous sodium sulphate .and evaporated to dryness under reduced pressure. The residue, crystallised from aqueous methanol, yielded 17u,20:20,21 bismethylenedioxy 3 ethoxy 6 hydroxyrnethylpregna-B,S-dien-1l-one, as flakes, M.P. 201 to 203 C., 175 (c. 0.77. in CHCl max.

Nuiol 'Ymax.

EXAMPLE 3 Preparation of 6-Hydroxymethyl-3-Methoxypregna-3,5- Dien-ZO-One 6-for-myl-3-methoxypregna-3,5-dien-20-one (5 g.) was hydrogenated in methanol ml.) over pne-reduced Haney nickel (5 ml. of settled suspension). The catalyst was removed by filtration, the filtrate was concentrated to small volume under vacuum and poured into water. The precipitated gum was extracted into ether, the extract was washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. 6-hydroxy1methyl-3- methoxypregna-3,S-dien-ZO-one crystallised from aqueous acetone as flakes, M.P. 112 to 114 0.,

A512? 250 ma (6 18,890)

a -96.5 (c. 0.87 in dioxan).

' EXAMPLE 4 Preparation of 17fi-Acezoxy-3-Eth0xy-6-Hydroxymethyl- Zu-Methylandr0sta-3,5-Diene 17p acetoxy 3 ethoxy 6 formyl 2a methylandrosta-3,5-diene (4 g.) in anhydrous tetrahydrofuran (50 ml.) was treated with lithium borohydri-de (0.6 'g.). The mixture was stirred for 10 minutes at room temperature, and then poured into water when the solids were collected, and purified from aqueous methanol. 1713- acetoxy 3 ethoxy 6 hydroxymethyl 2oz methylandnosta-3,5-die11e formed prisms, M.P. 140 to 141 C., [111 --138 (0.0181 in dioxan) EXAMPLE 5 Preparation of 17a-Acetoxy-6-Hy aroxymethyl-3-Methoxy-I 6-Methylenepregna-3,5-Dien-20-One 17a acetoxy 6 formyl 3 methoxy 16 methylenepreg-na-3,S-dien-ZOeone (1 g.) was dissolved in tetrahydrofur-an (10 ml.) containing lithium borohydride (0.2 g.), stirred for 1 0 minutes, and the mixture poured into water. The precipitated solids were collected and purified from aqueous methanol containing pyridine to give acetoxy 6 hydnoxymethyl 3 methoxy l6 7 methylenepregna-3,5-dien-20-one, needles, M.P. 171 to 173 C., [111 --252 (c. 1.04 in chloroform),

x332? 246.5 my (a 19,160) EXAMPLE 6 Preparation (of 3-Methoxy-6-Hydr0xymethyl-1 6 -M ethylpregna-3,5,16-Trien-20-0ne A223? 247 m (e 15,080) 7111 1;, 3350, 1650 and 1625 cm.-

EXAMPLE 7 Preparation of 17,8-Acetxy-6-Hydr0xymethyl-3-Meth- 0xyandrosta-3,5-Diene 17B acetoxy 6 formyl 3 methoxyandrosta 3,5-diene (20 g.) in dry tetrahydrofuran (150 ml.) was stirred with lithium borohydride (3 g.) for 10 minutes when the mixture was poured into water, and extracted with ether. The product solidified on removing the solvent. It was purified from aqueous methanol (containing a drop of pyridine) to give 17fl-acetoxy-6-hydroxymethyl-3-methoxyandrosta-3,S-diene, prisms, M.P. 144 to 149 C.,

m... 249 to 250 my. (6 19,750 113 -136 (c. 1.01 in dioxan).

EXAMPLE 8 Preparation of 17a-Acetoxy-d-Hydroxymethyl-3-Meth- 0xypregna-3,5-Dien-20-One 17a acetoxy 6 formyl 3 methoxypregna 3,5 dien-20-one g.) was added to a stirred suspension of lithium borohydride (0.5 g.) in anhydrous tetrahydrofuran (100 ml. After 5 minutes the mixture was poured into water. The product was extracted with ether and purified from aqueous methanol containing a dnop of pyridine to give 17a-acetoxy-6-hydroxymethyl-3-methoxypregna-3,5-dien-20-one in prisms, M.P. 197 to 201 C., [a] 137 (c. 0.80 in CHCl +1% pyridine),

1..., 249.5 Inn (6 19,660), 1239 1729, 1713, 164.6 and EXAMPLE 9 Preparation of 6-Hydr0xymethyl Cortisone Acetate 3- Enol Ethyl Ether CHzOAc EtO HiOH

Raney nickel sludge (1 ml.) was washed with methanol followed by ethyl acetate, then treated with ethyl acetate (10 ml.) and saturated with hydrogen at atmospheric pressure and room temperature. 21-acetoxy-3-ethoxy-6- formyl-17a-hydroxypregna-3,5 -diene-1 1,20-dione in methanol (50 ml.) was added, and hydrogenation continued until 180 ml. (1.2 mol.) of hydrogen had been absorbed.

The catalyst was removed, the filtrate was diluted with ether and washed with water, and the solvents were removed under reduced pressure to yield 6-hydroxymethyl cortisone acetate 3-enol ethyl ether, +18 (c. 0.74 in dioxan),

A 249.5 ma (6 12,800), 73,131? 3400, 1751, 1728, 1706,

1649 and 1619 cm.

EXAMPLE 10 Preparation of 3-Eth0xy-6-Hydr0xymethyl-I6a,17a-Isopropylidene-Di0xypregna-3,5-D[en-ZO-One 3 ethoxy 6 formyl 1604,1711 isopropylidencdioxypregna-3,5-dien-20-one (900 mg.) in pure dry dioxan (20 ml.) was treated with lithium cyanoborohydride (540 mg.) (Drehfall and Keil, I. Prak. Chem. 1958, 6, and the mixture heated at C. for 24 hours. The cooled mixture was poured into water and the gummy product extracted with ether. The extract was washed neutrafl (emulsification being overcome by addition of a little sodium chloride), dried (sodium sulphate) and evaporated in vacuo. The gummy solid thus obtained was crystallised from acetone/hexane containing a drop of pyridine to give 3-ethoxy-6-hydroxymethyl-16a,17misopropylidenedioxypregna-3,S-dien-ZO-one, prisms, M.P. 162 to 163 C., identical with the sample prepared as described in Example 1.

EXAMPLE 1 1 Preparation of 17/3 Acetoxy 6 Hydr0xymethyl-3-Meth- 0xyandr0sta-3,5-Diene (by hydrogenation of 17a-acetoxy-6-formyl-3-methoxyandrosta-3,S-diene with Raney nickel) Raney nickel ('1 g.) was washed twice with ethyl acetate by decantation. It was treated with ethyl acetate (10 ml.) and saturated with hydrogen at room temperature and atmospheric pressure. A solution of 17fl-acetoxy-6-formy1-3-methoxyandrosta-3,S-diene (3 g.) inmethanol '(50 ml.) was added, and hydrogenation was continued until the absorption of hydrogen reached 225 m1. (1.125 moles). The catalyst was removed by filtration, and the filtrate diluted with ether and washed with water. Removal of the solvent gave l7fi-acetoxy-6-hydlroxymethyl-3-methoxyandrosta-3,5 diene which was purified from aqueous methanol (70%) containing a drop of pyridine. The 6-hydroxymethyl derivative was obtained as prisms, M.P. to 149 C.

EXAMPLE 12 Preparation of 17 8-Acetoxy-3-Benzyloxy-6-Hydroxymethylandrosta-3,5-Diene max.

EXAMPLE 13 Preparation of 1 7a-Acetoxy-1 6-Ethylidene-6-Hydroxymethyl-3-Methoxypregnadj-Dien-ZO-O'ne Reduction of 17a acetoxy 16 ethylidene 6 formyl-3-methoxypregna-3,S-dien-ZO-one with sodium borohydride (as in Example 12) gave the corresponding 6-hydroxymethyl derivative,

A 250 mp (e-=20,100)

9 EXAMPLE 14 Preparation of 21-Acet0xy-6-Hydr0xymelhyl-1 7 a-H ydrxy-3- (2'-Hydroxyeth0xy -Pregna-3,5-Diene-11,20- Dione Hydrogenation of 21-acetoxy6-formyl-17a=hydroxy-3- (2'-hydroxyethoxy)-pregna-3,5-diene l1,20-dione according to. the process of Example 9 gave the G-hydroxymethyl derivative [111 +26 (c. 0.87 in dioxan) EXAMPLE 15 Preparation of 3-Eth0xy-6-Hydroxymethyl-17fi-Pr0pi0noxy-I 7a- (Pr0p-1 '-Ynyl)AWdr0sta-3,5-Diene A solution of 3-ethoxy-6-formyl-17B-propionoxy-17a- (prop-1-ynyl)androsta-3,5-diene (3 g.) in methanol (60 ml.) was treated with sodium borohydride (750 mg.) and left at room temperature for 30 minutes. Acetic acid (0.5 ml.) was added, followed by much water.

The precipitated solid was recrystallised firorn methanol to give 3-ethoxy-6-hydroxymethyl-17/3-propionoxy-l7a- (prop-1-ynyl) androsta-3,5-diene, prisms, M.P. 156 to 158 C.,

7x33 35011, 1730, 1650 and 1625 cm.- [0:] 207 (0. 1.06 in chloroform).

EXAMPLE 16 Preparation of 21-A cetoxy-l 7a-Hydr0xy-3-Meth0xy-6- Hydroxy-Methylpregna-3,5,9(1 1 )-Triene-20-One 21 acetoxy 17a hydroxy 3 methoxy 6 formylpregna-3,5,9( 11)-triene-'20-one (1.7 g.) was hydrogenated in methanol (100 ml.) and ethyl acetate (15 ml.) over Raney nickel (1 ml. settled sludge) which had been previously washed with methanol and ethyl acetate and saturated with hydrogen. Absorption of hydrogen was allowed to continue until 1.2 mols had been absorbed, when the catalyst was removed and the mixture diluted with ethyl acetate, washed with water, and the solvent removed under reduced pressure, to give 21-acetoxy-17ahydroxy 6 hydroxymethyl 3 methoxypi'egna 3,5,9 (1 1)-tn'en-20-one,

A 249 ma 19,000)

EXAMPLE 17 Preparation of 17B-Hydroxy-3-Methoxy-6-Hydroxymethylan'dr0sta-3,5-Diene Reduction of 17,8 hydroxy- 3 methoxy-6-formylandnosta-3,5-diene (1 g.) withsodium borohydride (0.1 g.) in tetrahydrofuran (12 ml.) and methanol (3 ml.) for 5 minutes, followed by dilution with water, gave the 6-hydroxy1nethyl derivative which was purified from aqueous methanol rm, 249111,. $19,200) EXAMPLE 18 Preparation of ZOfi-Acetoxy-S-Etiu0xy-6-Hydr0xymefhylpregna-3,5-Diene A solution of 20,3 acetoxy 3 ethoxy 6 formylpregna-3,5-diene (3.4 g.) in tetr-ahydrofuran (25 ml.) and methanol (5 ml.) was treated with sodium borohydride (0.25 g.) at room temperature for minutes. The product was isolated as described in Example 10 and crystallised from aqueous methanol containing a trace of pyridine to give 20fi acetoxy-3-ethoxy-6-hydroxymethylpregna-3,'5-diene, as needles, M.P. 142 to 144 C., -126 (c. 0.9 in dioxan) REL? 249 ma (6 19,120)

EXAMPLE 19' Preparation [of 1 7a-A cetoxy-6-Hydr0xymethyl-3-Methoxy-I 6a-Methylpregna-3,5-Din -20-One 17a acetoxy 6 formyl 3 methoxy 16a methv10 ylpregna-3,5-dien-20-one (1 g.) was dissolved in anhydrous tetrahydrofuran containing lithium borohydride (50 g.) and the solution stirred at room temperature for 5 minutes. The product was precipitated by the addition of water and crystallised from aqueous methanol to give 17a acetoxy 6 hydroxymethyl 3 methoxy 16a methylpregna-Ii,5-dien 20-one as plates M.P. 202 to 204 C., [111]) --147 (0. 0.52 in chloroform),

A212? 246.5 my (6 19,460)

EXAMPLE '20 21 -A cet0xy-6 -H y droxymethy [-3 -M eth oxypregna-3 ,5 Dien-ZO-One EtOH 0......

248.5 to 250.5 ma (6 18,280)

EXAMPLE 21 6-Hydr0xymethyl cortisone 17a,21-Diacetate 3-Methyl Enol Ether 0 Me i' --OAc A stirred solution of 6formy1contisone-17a,2l-diacetate methyl enol ether (486 mg.) in dry tetrahydrofuran (8 ml.) was treated with lithium borohydride in tetrahydrofuran (0.44 ml. of a solution containing 25 mg. borohydride per ml). After continuing to stir for five minutes, the solution was diluted with water and extracted with methylene chloride. Drying and evaporation of the extracts gave 176:,21-diacetoxy-6-hydroxymethy1-3-methoxypregna-3,5-diene-|11,20-dione as an amorphous material,

733 3600, 3450, 1615, 1660, 1750 and 1710 cm.

EXAMPLE 22 6-H ydroxymethy l-3-M ethoxy-l 7 fi-Acetoxy-I 9- N 0randr0sta-3 ,5 -Diene borohydride (0.15 g.) was added to a solution of 6 formyl-3-methoxy-17,3-acetoxy-19-uorandrosta-3,5- diene (1.0 g.) in dry tetnahydrofu-ran (7.5 ml.) and the mixture was stirred for 10 minutes and poured into water. Ether extraction and evaporation of the solvent yielded 1 1 6-hydroxymethyl 3 methoxy 17,8 acetoxy-l9-norandrosta-3,5-diene as a gum,

, 'y 1244, 1202, 1191, 1041, 1022 cm.-

EXAMPLE 23 6-H ydroxymethyl-3-Eth0xy-1 7 3-11 cetxy-19-N0r- Andr0sta-3,5-Diene Eto- 1203, 1189, 1159, 1126, 1115,1085, 1044, 1024, 999, 965, 910, 811, 690 emf.

EXAMPLE 24 3-Ethyl-Enol Ether of 6-H ydroxymethy lpregna-4,1 7 (20) Dien-3-One-21-Oate Ethyl Ester CH Me I A solution of the 3-ethyl enol ether of 6-formylpregna- 4,l7(20)-dien-3-one-2l-oate ethyl ester (1.0 g.) in tetrahydrofuran (10 ml.) was added to a suspension of lithium borohydride (0.15 g.) in tetrahydrofuran (5 ml.) at room temperature, and the mixture was stirred for minutes and then poured into water. Ether extraction and evaporation of the solvent yielded the 3-ethyl-enol ether of 6 hydroxymethylpregna-4,17(20)-dien-13-one-21 oate ethyl ester, 1710, 1656, 1647, 1622 cm.-

EXAMPLE 25 }9-(1 718-H ydr0xy-3-Eth0xy-6-H ydroxynzethylanarosta-3,5 Dian-1 7a-Yl)Pr0pi0nic Acid Lactone B (17,8 hydroxy-S-ethoxy-6- formylandrosta-3,5-dienl7a-yl)propionic acid lactone (1.0 g.) in dry tetrahydrofuran (10 ml.) was treated with lithium borohydride (150 mg.) and the mixture stirred for 10 minutes after which it was poured into water and the product isolated with ether. The 6-hydroxymethyl derivative was obtained as a gum,

723i? 3600, 1770, 1655, 1625 cm.

1 2 EXAMPLE 26 2] -Acetoxy-1 7a-Hydroxy-6-Hydroxymethyl-3- M eth0xypregna-3,5 -Diene-1 1 ,20-Dione 21 acetoxy 6-formyl-17a-hydroxy-3-methoxypregna- 3,5-diene-ll,20-dione (4 g.) was hydrogenated over a prereduced 5% platinum-charcoal catalyst (0.5 g.) in methanol (60 ml.) containing sodium acetate (0.5 g.). The absorption of hydrogen almost ceased at one mol, when the catalyst was removed by filtration, and the filtrate diluted with water to turbidity. The crystalline material which separated out was purified from aqueous methanol +1% pyridine to give 21-acetoxy-117a-hydroxy-6-hydroxymethyl-3-methoxypregna-3,S-diene-l1,20-dione in solvated crystals, M.P. 126 to 130 C., [511 10 (c. 1.0 in dioxan), A 248.5 mp (e=15,900) in ethanol.

EXAMPLE 27 6-Hydroxymethyltestololactone 3-Enol Methyl Ether MeO- -formyltestololactone 3-enol methyl ether (1 g.) in methanol 10 ml.) was treated with sodium borohydride (100 mg.) for 5 minutes then water was added until the product crystallised out. Purification from acetone/hexane gave 6-hydroxymethyltestololactone 3-enol methyl ether, A 250 mp. (e=19,200) in ethanol.

EXAMPLE 28 1101,17B-Diacet0xy-6-Hydr0xymethyl-3- M eth0xyandr0sta-3,5-Diene 1112,1713 diacetoxy 6 formyl 3 methoxyandrosta- 3,5-diene (250 mg.) reduced by the process of Example 27 gave 11a,17fl-diacetoxy-6-hydroxymethyl-3-methoxyandrosta-3,5-diene, prismatic needles from aqueous methanol and 1% pyridine, M.P. 162 to 166 C., [011 216 (c. 0.87 in dioxan) A 249.5 m, (e=18,950) in ethanol.

EXAMPLE 29 6-Hydroxymethylc0rtisone 17,21-Acet0nide 3-En0l Methyl Ether MeO- 6-formylcortisone 17,21-acetonide 3-enol methyl ether (900 mg.) was hydrogenated in methanol ml.) with Raney nickel catalyst (1 ml. settled sludge, Washed with methanol and pre-hydrogenated) until absorption ceased at ml. The catalyst was removed by filtration and the filtrate diluted with Water until crystallisation began. The product was purified from aqueous methanol +1% pyridine to give 6-hydroxymethylcortisone 17,21-acetonide 3- enol methyl ether, feathery crystals, M.P. 174 to C.,

[111 -45 (c. 0.93 in dioxan), A 248 m (5: 17,000 in ethanol.

1 3 EXAMPLE 30 21-Acet0xy-6-Hydr0xymethyl-3-Methoxypregna- 3,5,17(20)-Trien-11-One CHrOAc Me I MeO-

HgOH

OOMe Me I Me I 0A0 Mao- HIOH 15a acetoxy 6 formyl 3 methoxypregna 3,5- diene-ZO-one hydrogenated over platinum-charcoal by the process of Example 26, gave 15u-acetoxy-6-hydroxymethyl-3-methoxypregna-3,5-dien-20-one, A 249.5 mi

"in ethanol.

EXAMPLE 32 1 7B-A cetoxy-3-Ethoxy-6-Hydroxymethylandrosta- 3,5-Dime 175 acetoxy 3 ethoxy 6 :formyland-rosta 3,5 diene (10 g.) was treated in methanol (50 ml.) with sodium borohydride (0.5 g.) and stirred for 10 minutes, then the solution was diluted with water until crystallisation began. Purification-from aqueous methanol and 1% pyridine gave 175-acetoxy-3-ethoxy-6-hydroxymethylandrosta-3,5-diene, flakes, MP. 114 to 119 C.,-[M 163 (c. 0.90 in dioxan), A 251 m (e=20,050) in ethanol. 1

EXAMPLE 33 1 7B-A cet0xy-3- (,B-Ethoxyethoxy -6-Hydroxymethylandr0sta-3,5-Diene 0A0 Me EtO CHaCHrO- HaOH 14 176- acetoxy 3 (,8- ethoxyethoxy) 6 formylandrosta-3,5-diene (10 g.) was treated in methanol (50 ml.) with sodium borohydride (0.5 g.) and stirred for 10 minutes, then the solution was diluted with water until crystallisation began. Purification gave 17fi-acetoxy-3-(fi-ethoxyethoxy) 6 hydroxy-methylandrosta-3,S-diene, Amax.

250 m (e=20,170) in ethanol.

EXAMPLE 34 1 6 a, 17/3-Ep0xy-6-Hydr0xymethyl-3-Meth0xypregna-. 3,5-Din-20-One 6 formyl 16a,17a epoxy 3 methoxypregna 3,5- diene-ZO-one was hydrogenated over platinum-charcoal by the process of Example 26, to give 16u,17a-epoxy-6-hydroxymethyl-3-methoxy-pregna-3,5-dien-20-one, A 249 m (e=20,100) in ethanol.

EXAMPLE 35 3-Benzyl0xy-6-Hydr0xymethylandr0sta-3,5- Dien-l 75-01 3-benzyloxy-6-formylandrosta-3,5-dien-17-one (2 g.) was reduced with sodium borohydride (0.4 g.) in methanol (20 ml.) for 15 minutes, then water was added until the product began to crystallise. Purification from aqueous methanol+1% pyridine gave 3-benzyloxy 6 hydroxymethylandrosta-3,5-dien--01, A 25 0 m (6: 19,890) in ethanol.

EXAMPLE 36 6-H ydroxymethyl-3-M ethoxypreg na-ib' Diene-l 1,20-Di0ne 6 formyl 3 methoxypregna 3,5 diene 11,20- dione hydrogenated over platinum-charcoal by the process of Example 26 gave 6-hydroxymethyl-3-methoxypregna- 3,5-diene-11,20-dione, A 248.5 m (e: 19,740) in ethanol.

EXAMPLE 37 6 -H ydr oxymethy l-3-M ethoxyandrosta-3,5 -Dien-1 7-0ne 6 formyl 3 methoxyandrosta 3,5 diene 17 one (780 mg.) in ethanol (60 ml.) containing sodium acetate (300 mg.) was reduced with hydrogen in the presence of 5% platinum charcoal (300 mg). After 5 hours uptake of hydrogen stopped when 1.05 mol had been absorbed. The catalyst was removed by filtration and water was added to the filtrate until crystallisation began. The prodnot was purified from aqueous methanol and 1% pyridine to give 6-hydroxymethyl-3-methoxyandrosta-3,5-diene-17- one, needles, MP. 143 to 146 C., [M 111 (c. 0.91

r in dioxan), A 249 mp. (e=19,000) inethanol.

EXAMPLE 38 21-Acetoxy-11fl,17a-Dihydroxy-6-Hydrqxymethyl-3- M eth0xypregna-3,5 -Dien-20-0ne 21 acetoxy 6 formyl 113,170: dihydroxy 3- methoxypregna-3,5-dien-20-one (1 g.) was hydrogenated in ethanol (15 ml.) containing sodium acetate (0.5 g.) over a 5% platinum-charcoal catalyst (0.3 g.) until one mole of hydrogen had been absorbed. The catalyst was removed by filtration and the solution poured into water to precipitate the product. Purification from aqueous methanol gave 21-acetoxy-115,17a-dihydroxy-6-hydroxymethyl-3-methoxypregna-3,S-dien-ZO-one, A 249.5 m (e=19,800) in ethanol.

1 EXAMPLE 39 21-Acetoxy-9a-Fluor0-l 1 6,1 7a-Dihydr0xy-6-Hydr0xymethyl-3-Methoxypregna-3,5-Dien-ZO-One OHnOAc 00 Me ---0H Me i l l H F MGO HaOH

EXAMPLE 4O 6-Hydr0xymethyl Derivative of 17a-Methyltest0sterone 3-En0l Methyl Ether A solution of 17fl-acetoxy-6-formyl-3-methoxy-17amethylandrosta-3,5-diene (3.7 g.) in dry tetrahydrofuran (200 ml.) was treated with lithium aluminium hydride (3.5 g.). The mixture was heated under reflux for 3 hours, cooled, excess reducing agent was destroyed by the addition of a little acetone, and the product isolated with methylene dichloride. Purification from acetone/hexane gave 17,8 hydroxy 6 hydroxy methyl 3 methoxy- 17a-methylandrosta-3,S-diene, tablets, M.P. 109 to 111 C., l42 (c. 1.02 in chloroform).

We claim:

1. A process for the preparation of 3-enol ethers of 6-hydroxymethyl-3-oxo-A -steroids having in rings A and B of the steroid nucleus, the structure CHaOH where R is selected from the group consisting of O-alkyl, O-hydroxyalkyl, O-cycloalkyl, O-alkaryl and a functional derivative thereof which process comprises reducing the corresponding 3-eno1 ether of a 6-formy1-3-oxo-A -steroid having in rings A and B of the steroid nucleus, the structure CHO

a a Et where R is selected from the group consisting of O-alkyl, O-hydroxyalkyl, O-cycloalkyl, O-alkaryl and O-alkylalkoxy.

7. 21 acetoxy 3 ethoxy 17cc hydroxy 6 hydroxymethyl pregna 3,5 diene 11,20 dione.

8. 21 acetoxy 17a hydroxy 3 [e hydroxyethoxy] 6 hydroxymethylpregna 3,5 diene 11,20- dione.

9. 1701,21 diacetoxy 6 hydroxymethyl 3 methoxypregna 3,5 diene 11,20 dione.

10. l7,20:20,21 bismethylenedioxy 3 ethoxy 6- hydroxy-methylpregna-3 ,5 -diene l'l-one.

11. 17a. acetoxy 6 hydroxymethyl 3 methoxy- 16-methylenepregna-3,S-dien-ZO-one.

12. 17a acetoxy 6 hydroxymethyl 3 methoxypregna-3,5-dien-20-one.

13. 17a acetoxy 6 hydroxymethyl 3 methoxyl6a-methylpregna-3,S-dien-ZO-one.

14. 3-ethoxy-6-hydroxymethyl 16a,17a-isopr0pylidenedioxypregna-3,5-dien-20-one.

15. 6-hydroxymethyl-3-methoxypregna-3,S-dien-ZO-one.

16. l7fi-acetoxy-3-ethoxy-6-hydroxymethyl Zen-methylandrosta-3,5-diene.

17. 17,8 acetoxy-fi-hydroxymethy1-3-methoxyandrosta- 3,5-diene.

18. 3-ethoxy-6-hydroxymethyl 17(3 propionoxy-lh- (prop-1'-ynyl)androsta-3,5-diene.

19. 17B-acetoxy-3-benzyloxy-6-hydroxymethylandrosta- 3,5-diene.

20. 17/3 acetoxy-3-ethoxy 6 hydroxymethyl-l9-norandrosta-3,5-diene.

21. 17/3-acetoxy-3-methoxy 6 hydroxymethyl-l9-norandrosta-3,5-diene.

22. 6-hydroxymethyl 3 methoxy l6 methylpregna- 3,5,16-trien-20-one.

23. 20B-acetoxy 3 ethoxy 6 hydroxymethylpregna- 3,5-diene.

24. 3 -ethoxy 6 hydroxymethylpregna 3,5,17(20)- trien-2l-oic acid ethyl ester.

25. 6-hydroxymethyl 3 methoxyandrosta-3,S-dien-17- one.

26. 21 acetoxy 6 hydroxymethyl-3-methoxypregna- 3,5-dien-20-one.

27. 6-hydroxymethyltestololactone 3-enol methyl ether.

28. 21-acetoxy 17a hydroxy-6-hydroxymethyl-3-methoxypregna-3,5-diene-1 1,20-dione.

r29. 6-hydroxymethylcortisone 17,21-acetonide 3-enol methyl ether.

30. 17B-acetoxy-3-ethoxy 6 hydroxymethylandrosta- 3,5-diene.

31. 110:,1713-di2lC6t0XY 6 hydroxymethyl-3-methoxyandrosta-3,5-diene.

References Cited in the file of this patent Gilman: Organic Chemistry, vol. 1, 2nd ed., pp. 803-5, 1953, John Wiley and Sons, New York, NY.

Drehfall and Keil: J. Prak, Chem. 6, (1958). 

6. 3-ENOL ETHERS OF 6-HYDROXYMETHYL-3-OXO-$4-STEROIDS, SAID 3-ENOL ETHERS HAVING IN RING A AND B OF THE STEROID NUCLEUS THE STRUCTURE 